US8394141B2 - Connective-tissue-based or dermal-tissue-based grafts/implants - Google Patents
Connective-tissue-based or dermal-tissue-based grafts/implants Download PDFInfo
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- US8394141B2 US8394141B2 US12/807,599 US80759910A US8394141B2 US 8394141 B2 US8394141 B2 US 8394141B2 US 80759910 A US80759910 A US 80759910A US 8394141 B2 US8394141 B2 US 8394141B2
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Definitions
- the present invention is directed to the field of biocompatible matrices for use in forming devices for implantation in animals and humans. More particularly, the present invention is directed to an implantable composition or a tissue graft/implant formed from an allogeneic biocompatible human muscle matrix that is capable of carrying other implantable materials or that can be formed into a plurality of tissue implants or compositions having different properties and different shapes.
- the present invention is useful because it provides an implantable composition or, device that is versatile in its ability to be formulated into a variety of implants or grafts that are useful in the treatment of a variety of medical conditions in patients.
- devices In the field of biomedical implants, devices have been made that range far afield from the biological components found in the human body. For example, many devices that are intended as bone substitutes are made from metals such as titanium, or biocompatible ceramics. A problem in such instances is that they have different material properties than the host tissue causing the devices to loosen at the interface between the host tissue and the device itself
- allograft bone in place of metal or ceramic implants.
- implants made of allograft bone can act as the scaffolding for remodeling by the host.
- Such implants function by being both structurally and biologically similar to the host tissue. Further, they allow cellular recruitment through the natural openings in the matrix and allow the graft to be replaced by natural host bone.
- allograft bone is very useful, it is limited by the intended clinical use. Thus, it is particularly useful for spinal fusions where the spacings between the vertebrae are relatively fixed and well known.
- injuries come in a variety of shapes and sizes that present a logical limitation on the availability of an ideal graft to fill the defect.
- Another example area where biocompatible implants are important is in replacement skin for burn victims. Histocompatibility, remodeling and safety are considerable problems in utilizing allograft skin. To avoid this problem and the shortage of viable donor skin, a surgeon often removes skin from another part of the patient and transplants it to the area of need. While such skin is non-antigenic, it causes significant morbidity to the patient at the site of removal. Moreover, depending upon the size of the wound or burn, there may not be sufficient skin on the patient to satisfy the need. To alleviate this problem, at least one company will culture the patient's skin cells on a collagen matrix to form a transplantable layer of skin. However, the culture time is relatively extensive and the patient's wound or burn is exposed while awaiting the graft.
- the grafts generated in this way do not mimic normal skin, which is composed of multiple cell types and structures. Accordingly, there is a need in the art for an implantable biocompatible matrix that can be formulated into a sheet and cut to size and that can act as scaffolding to allow the infiltration of a variety skin cells from adjacent tissue that will lay down a compatible and natural replacement structure in the shape of the implant, while absorbing the implant itself.
- the present invention is directed to a composition comprising a matrix suitable for implantation in humans, comprising defatted, shredded, allogeneic human muscle tissue that has been combined with an aqueous carrier and dried.
- a composition comprising a matrix suitable for implantation in humans, comprising defatted, shredded, allogeneic human muscle tissue that has been combined with an aqueous carrier and dried.
- the composition of the present invention is sufficiently dried to so as to be able to be handled. More typically, it is dried to a moisture content of about 3% or less.
- any human muscle is suitable for use in the compositions or tissue graft/implant of the present invention, including smooth muscle and striated muscle.
- the human muscle tissue that is employed is striated muscle, such as skeletal muscle or cardiac muscle. More preferably, the muscle tissue employed is skeletal muscle tissue.
- a composition or tissue graft/implant of the present invention that is particularly suited for treating bone trauma, bone disease or bone defects, for providing artificial arthrodeses, or for other treatment where new bone formation is desired, further comprises particles of DBM, mineralized bone matrix, CCC, crushed cancellous chips, tricalcium phosphate, hydroxyapatite, or biphasic calcium phosphate dispersed in the matrix.
- a preferred composition or tissue graft/implant of the present invention that is particularly suited for treating bone trauma, bone disease or bone defects, for providing artificial arthrodeses, or for other treatment where new bone formation is desired, further comprises particles of DBM, mineralized bone matrix, CCC, crushed cancellous chips, tricalcium phosphate, hydroxyapatite, or biphasic calcium phosphate dispersed in the matrix, in combination with a therapeutically effective amount of a growth factor selected from the group consisting of bone morphogenic protein (BMP), LIM mineralization protein (LMP) and RUNX-2.
- BMP bone morphogenic protein
- LMP LIM mineralization protein
- RUNX-2 a growth factor selected from the group consisting of bone morphogenic protein (BMP), LIM mineralization protein (LMP) and RUNX-2.
- composition and the tissue graft/implant of the present invention comprise a matrix that is formed from the fibers of defatted, shredded, allogeneic human muscle tissue.
- This fibrous structure is advantageous because the resulting matrix that is formed is porous and particularly well suited both for the infiltration by colonizing cells (e.g., osteoconduction), and for the storage and slow release of seeded cells, growth factors (as described above), and chemotactic agents to attract desired cells (e.g., osteoinduction).
- composition or tissue graft/implant of the present invention is to be used as a tissue graft for skin, it is optionally seeded with dermatocytes, more typically with dermatocytes and melanocytes.
- tissue grafts and implants of the present invention exhibit a great degree of tensile strength. They are readily stitchable and retain a majority of their tensile strength even when rehydrated.
- tissue grafts and implants of the present invention are moldable and suitable for filling in irregular gaps or holes in the tissue to be repaired. Typically, the hydrated tissue is press fitted by the surgeon into the defect or cavity to be filled.
- the tissue graft/implant of the present invention be utilized with a load-bearing member used in a spinal fusion.
- Suitable load bearing members include hollow spinal cages, hollow dowels, C-shaped and D-shaped spacers and other devices known in the art, having a pocket, chamber or other mechanism for retaining the tissue graft/implant of the present invention.
- the load-bearing member has a compressive strength of at least about 1,000 N. More typically, when utilized between lumbar vertebrae, the load-bearing member has a compressive strength of 3,000; to 11,000; N. When utilized between cervical vertebrae, the load bearing member has a compressive strength of about 1,000; to 3,000 N.
- Suitable load bearing members are known in the art and described in multiple U.S. patents, including, for example in U.S. Pat. Nos. 5,522,899, 5,785,710, 5,776,199; and 5,814,084, 6,033,438, 6,096,081, each of which is hereby incorporated by reference in its entirety
- the skeletal muscle-based implantable devices and compositions of the present invention have hemostatic action and cause platelet activation. This is a particular advantage during surgical procedures wherein patient bleeding is a well known problem.
- the present invention is directed to a method for making a (muscle-based) composition or a tissue implant suitable for treating an injury or a surgical or medical condition in a human patient, wherein the tissue implant comprises a matrix of allogeneic human muscle.
- the method comprises the steps of:
- the matrix of allogeneic human muscle comprises from about 1% to about 100% of the final weight of the composition or implant, more typically, from 50% to about 99% of the final weight of the implant, even more typically from 75% to about 99% of the final weight of the implant.
- the DBM, mineralized bone matrix, CCC, crushed cancellous chips, tricalcium phosphate, hydroxyapatite, or biphasic calcium phosphate or a combination thereof typically constitute from 1% to 99%, more typically 50% to 99%, most typically from 90% to 99% of the dry weight of the composition or implant.
- the tissue implant When the tissue implant contains tendon, it is tougher, and stronger than the digested human muscle matrix alone and is particularly suited as a dressing for a wound or burn that will become infiltrated with skin cells and allow for development of a replacement skin layer that will cover the wound or burn.
- the ratio of tendon to intermediate composition ranges from 1:99; to 99:1; by dry weight. Typically, the range is 10:90; to 90:10; more typically, the range is 25:75; to 75:25. While the above discussion is in relation to “tendon,” which is a preferred source of collagen for this invention, it is intended that any collagen source be used, including fascia, ligament, or dermis.
- the slurry is poured into a mold for formation of an implantable tissue matrix of any size or shape.
- the slurry can be combined with other agents, such as DBM, CCC or a collagen (e.g., tendon, fascia) slurry before being poured into the mold.
- FIG. 1 is a photograph showing the fluffy fibrous texture of shredded, defatted allogeneic human muscle for use in making the intermediate composition (muscle slurry) of the present invention.
- FIGS. 2A-2C are photographs of tissue implants in the form of a sponge that were made from the muscle slurry of the present invention.
- FIGS. 4A and 4B are photographs of tissue implants/grafts in the form of a thin film that were made from the muscle slurry of the present invention.
- the film was formed from the muscle slurry without an additive.
- the film was made from a mixed slurry comprising a 50:50; ratio of muscle tissue to tendon tissue.
- the present invention has multiple embodiments.
- the present invention is directed to a composition that provides a biocompatible, non-antigenic matrix and scaffolding material for tissue regeneration in humans. More specifically, the present invention is directed to a composition comprising a matrix suitable for implantation in humans, comprising defatted, shredded, allogeneic human muscle tissue that has been combined with an aqueous carrier and dried.
- the composition of the present invention is sufficiently dried to so as to be able to be handled. More typically, it is dried to a moisture content of about 3% or less.
- composition (and implants) of the present invention must be treated to remove any antigenic proteins, which may generate a rejection of the implant. It also must be treated to remove any bacteria and viruses. Suitable processes for removing antigenic proteins and sterilizing to neutralize any bacteria and viruses are known in the art. See U.S. Pat. No. 5,846,484, entitled “Pressure flow system and method for treating a fluid permeable workpiece such as a bone,” which issued to Scarborough, et al. on Dec. 8, 1998.
- the present invention is directed to a tissue graft/implant suitable for implantation in humans comprising a matrix of defatted, shredded, allogeneic human muscle tissue that has been combined with an aqueous carrier and dried in a predetermined shape.
- the tissue graft/implant of the present invention is made in various shapes including that of a strip, a sheet, a disc, a molded 3D shaped object, a plug, a sponge, and a gasket.
- a preferred shape is a sponge. Any of these objects may include a cavity, a pouch, a hole, a post, a hook, or a suture.
- DBM demineralized bone matrix
- CCC cortical cancellous chips
- crushed cancellous chips lyophilized and shredded muscle or collagen fibers, growth factors, antibiotics, stem cells, or other additives.
- the human muscle tissue that is employed in the composition and tissue graft/implant of the present invention is striated muscle, such as skeletal muscle or cardiac muscle, more preferably, skeletal muscle tissue.
- a composition or tissue graft/implant of the present invention that is particularly suited for treating bone trauma, bone disease or bone defects, for providing artificial arthrodeses, or for other treatment where new bone formation is desired, further comprises particles of DBM, mineralized bone matrix, CCC, crushed cancellous chips, tricalcium phosphate, hydroxyapatite, or biphasic calcium phosphate dispersed in the matrix.
- particles of DBM or CCC or both are added to the composition or to the tissue graft/implant of the present invention when the composition or implant is being used as a scaffold to obtain bone regeneration or remodeling at the site of implantation.
- the mean size of the particles of DBM and mineralized bone matrix are typically from 150; microns to 900; microns, more typically from 250; microns to 800 microns, most typically from 400; to 500; microns.
- the CCC and crushed cancellous chips are utilized in a larger particle size than the DBM.
- the mean particle size for CCC is typically 0.5; mm to 5; mm, more typically 1; mm to 3; mm, and even more typically from 1.5; mm to 2.5; mm.
- a preferred composition or tissue graft/implant of the present invention that is particularly suited for treating bone trauma, bone disease or bone defects, for providing artificial arthrodeses, or for other treatment where new bone formation is desired, further comprises particles of DBM, mineralized bone matrix, CCC, crushed cancellous chips, tricalcium phosphate, hydroxyapatite, or biphasic calcium phosphate dispersed in the matrix, in combination with a therapeutically effective amount of a growth factor selected from the group consisting of bone morphogenic protein (BMP), LIM mineralization protein (LMP) and RUNX-2.
- BMP bone morphogenic protein
- LMP LIM mineralization protein
- RUNX-2 a growth factor selected from the group consisting of bone morphogenic protein (BMP), LIM mineralization protein (LMP) and RUNX-2.
- BMP A preferred growth factor is BMP.
- BMP encompasses a family of well-known naturally occurring proteins (BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-13; and BMP-14) that are involved in skeletal formation.
- BMP2; or BMP2A is a 396 amino acid (aa) dimeric protein in human (chr 20p12) that belongs to the TGF-beta superfamily of structurally related signaling proteins. It is involved in cartilage and bone formation during embryogenesis, but may have additional functions in morphogenesis as implied by its expression in various organs and embryonic tissues. It is abundant in bone, lung, spleen, and colon.
- Recombinant human BMP-2 (rhBMP-2) consists of two 115 amino acid chains that lack the natural N-terminus and that are bonded by a disulfide bond into a homodimeric protein with an apparent molecular weight of 26; kDa.
- the rh-BMP-2 lacking the natural N-terminus, has 15-20; times specific activity of the wild-type BMP-2.
- Methods for isolating BMP from bone are described in U.S. Pat. No. 4,294,753 to Urist and Urist et al., PNAS 371, 1984.
- BMP is obtained by packing fresh fragments of bone into a cavity in an implant that is designed for receiving such packing. However, the amount of BMP in such packing is variable.
- the BMP be a recombinant human BMP such that its activity is known.
- Recombinant human BMPs are commercially available as described below or prepared as described and known in the art, e.g., in U.S. Pat. No. 5,187,076; to Wozney et al.; U.S. Pat. No. 5,366,875; to Wozney et al.; U.S. Pat. No. 4,877,864; to Wang et al.; U.S. Pat. No. 5,108,932; to Wang et al.; U.S. Pat. No. 5,116,738; to Wang et al.; U.S. Pat. No.
- BMP3/Osteogenin/BMP-3A is a 472aa protein in human (chr 4p14-q21), highly expressed in lung, ovary and small intestine. Its function is involved in the cartilage and bone formation. BMP3; and BMP2; genes map to conserved regions between human and mouse. Sequences or methods of isolating BMP-3; are disclosed in Kawabata, M et al. (1998) Cytokine and Growth Factor Reviews 9: 49-61;; Ebendal, T et al. (1998), J. Neurosci. Res. 51: 139-146;; Reddi, A. H (1998), Nature Biotechnology 16: 247-252; Daluiski, A et al. (2001), Nature Genetics 27: 84;; and Bahamonde, M. E et al. (2001) Bone and Joint Surgery 83-A (suppl 1): S156, each of which is incorporated herein by reference.
- BMP-3B/GDF-10 a 478aa protein in human (Chr 10q11.22), belongs to a group of proteins that can induce endochondral bone formation in adult animals, it is closely related in sequence to BMP3; with 44% homology.
- the amino acid sequences of human and rat BMP-3b precursor proteins are 83% similar, whereas the mature proteins show 98% identity.
- BMP-3B is mainly expressed in femur, brain, lung, pancreas and testis. Sequences or methods of isolating BMP-3; are disclosed in Hino. J et al. (1996) Biochem Biophysic. Res.Commun. 223; (2), 304-310;; Cunningham, N. S. et al.
- BMP4/BMP-2B is a 408aa protein (Chr.14q22) and vital regulatory molecule that functions throughout development in mesoderm induction, tooth development, limb formation, bone induction, and fracture repair. In human it is expressed in lungs, kidney and is secreted into the extracellular matrix. Sequences or methods of isolating BMP-4 are disclosed in Hogan et al., (1996) Gene Dev., 10:1580-1594;; Kawabata, M et al. (1998) Cytokine and Growth Factor Reviews 9: 49-61;; Ebendal, T et al. (1998), J. Neurosci. Res. 51: 139-146;; Reddi, A.
- BMP5 is a 454aa protein mainly expressed in lungs and liver. (Chr 6).
- the Bmp5 gene is expressed at the earliest stages of skeletal development in small, local patterns that prefigure the shapes of future skeletal elements.
- BMP5, BMP6, and BMP7 Based upon a high degree of amino acid sequence homology, BMP5, BMP6, and BMP7; constitute a subfamily within the BMPs. Sequences or methods of isolating BMP-5; are disclosed in Kawabata, M et al. (1998) Cytokine and Growth Factor Reviews 9: 49-61, Ebendal, T et al. (1998), J. Neurosci. Res. 51: 139-146;; Reddi, A. H (1998), Nature Biotechnology 16: 247-252, each of which is incorporated herein by reference.
- BMP6 is a 571(D protein with 513aa in human (chr 6p24). Increased production of BMP6; is mediated by the skeletal effects of estrogen on bone and cartilage.
- BMP-6 differs from other members of the BMP family by its concentration in cartilage of the fetus. Sequences or methods of isolating BMP-6; are disclosed in Kawabata, M et al. (1998) Cytokine and Growth Factor Reviews 9: 49-61;; Ebendal, T et al. (1998), J. Neurosci. Res. 51: 139-146;; Reddi, A. H (1998), Nature Biotechnology 16: 247-252;; and Celeste, A et al. (1990) PNAS. 87: 9843-9847, each of which is incorporated herein by reference.
- BMP7 or OP1a 431-amino acid polypeptide (chr 20) that includes a secretory signal sequence, expressed in kidney, bladder and brain.
- BMP-7 induces cartilage and bone formation. It also plays a role in calcium regulation and bone homeostasis. Sequences or methods of isolating BMP-7; are disclosed in Sampath, T. K et al. (1990) JBC 265: 13198-13205, Reddi, A. H et al. (1998), Nature Biotechnology 16: 247-252; Helder, M. N et al (1995) J. Histochem. Cytochem 43: 1035-1044;; and Godin, R. E et al. (1998) Development 125: 3473-3482, each of which is incorporated herein by reference.
- BMP13/CDMP-2/GDF-6 is a cartilage derived morphogenetic protein (CDMP) with 436aa precursor sequence, that is cleaved to a 120aa polypeptide mature chain. Like all BMPs, it exists as homodimer subunits linked with a disulphide bond. This protein is predominantly expressed in long bones during human embryonic development. Sequences or methods of isolating BMP-13; are disclosed in Chang, S. C et al. (1994) JBC Vol. 269; (45), 28227-28234;; Paralkar V. M et al. (1998) JBC 273; (22) 13760-13767;; Tomaski SM et al. (1999) Arch Otolaryngol Head Neck Surg. 125; (8) 901-906.
- CDMP cartilage derived morphogenetic protein
- BMP14/CDMP-1/GDF-5 is a 501aa precursor protein (chr 20q11.2) with a 121aa mature chain. It is predominantly expressed in long bones during embryonic development and is involved in bone formation. Sequences or methods of isolating BMP-14; are disclosed in Chang, S. C et al. (1994) JBC Vol. 269; (45), 28227-28234;; Paralkar V. M et al (1998) JBC 273; (22) 13760-13767;; and Tomaski S M et al. (1999) Arch Otolaryngol Head Neck Surg. 125; (8) 901-906, each of which is incorporated herein by reference.
- BMP-2 Human recombinant BMP-2; is commercially available from a plurality of sources, including Genetics Institute, Inc., Andover, Mass., Abbott Laboratories, North Chicago Ill., and Yamanouchi Pharmaceutical Co., Japan.
- the preferred BMPs are recombinant human BMP-2; (rhBMP-2), recombinant human BMP-4; (rhBMP-4), recombinant human BMP-7; (rhBMP-7) and heterodimers thereof. rhBMP-2; is most preferred.
- TGF- ⁇ transforming growth factor- ⁇
- FGF fibroblast growth factor
- PDGF platelet-derived growth factor
- ILGF insulin-like growth factor
- composition and the tissue graft/implant of the present invention comprise a matrix that is formed from the fibers of defatted, shredded, allogeneic human muscle tissue.
- This fibrous structure is advantageous because the resulting matrix that is formed is porous and particularly well suited both for the infiltration by colonizing cells, and for the storage and slow release of seeded cells, tissue growth factors (as described above), and chemotactic agents to attract desired cells.
- composition or implant/tissue graft of the present invention be combined with seeded cells, a tissue growth factor, or a chemotactic agent, or a combination thereof.
- composition or tissue graft/implant of the present invention is to be used as a tissue graft for skin, it is optionally seeded with fibroblasts, more typically with fibroblasts, and melanocytes.
- the composition or tissue graft further comprise a growth factor suitable for inducing the growth of the fibroblasts and/or melanocytes.
- Suitable growth factors include a fibroblast growth factor (FGF), such as FGF-1; of FGF-2, epidermal growth factor, transforming growth factor-a (TGF-a), transforming growth factor- ⁇ (TGF- ⁇ ), platelet derived growth factor (PDGF) or a combination thereof.
- FGF fibroblast growth factor
- TGF-a transforming growth factor-a
- TGF- ⁇ transforming growth factor- ⁇
- PDGF platelet derived growth factor
- composition or tissue graft/implant of the present invention When the composition or tissue graft/implant of the present invention is to be used to treat bone trauma, disease and defects, for artificial arthrodeses and for other treatment where new bone formation is desired, it is optionally seeded with osteogenic cells.
- the composition or tissue graft/implant of the present invention is seeded with stem cells that will provide a natural distribution of the native cells necessary for restoration of the injury or defect at the site of implantation.
- the implant/graft of the present invention comprising a matrix of digested allogeneic human muscle was made in various shapes including that of a strip, a sheet, a film, a disk, a molded 3D shaped object, a plug, a sponge, and a gasket. Any of these objects may include a cavity, a pouch, a hole, a post, a hook, or a suture. Any of these objects may be made with or without the addition of DBM, CCC, lyophilized and shredded muscle tissue, collagen fibers, growth factors, antibiotics, stem cells, or other additives.
- the dimensions are typically from about 10; mm to 500; mm long, by 10; mm to 200; mm wide and 1; mm to 10; mm thick, more typically from about 15 mm to 200; mm long by 15; mm to 100; mm wide and 2; mm to 8; mm thick, even more typically from about50; mm to 90; mm long by 15; mm to 35; mm wide and 2; mm to 5; mm thick.
- the cross section of such a strip may take any shape including a rectangle, square, triangle, other polygon, circle, half circle, ellipse, or partial ellipse.
- the dimensions are typically from about 20; mm to 300; mm by 10; mm to 100; mm and 1; mm to 10; mm thick, more typically from about 30 mm to 150; mm by 20mm to 70; mm and 1.5; mm to 8; mm thick, even more typically from about 50; mm to 100; mm by 25; mm to 50; mm and 2; mm to 5; mm thick.
- the dimensions are typically from about 20; mm to 300; mm by 10; mm to 100; mm and 0.1; mm to 5; mm thick, more typically from about 30 mm to 150; mm by 20mm to 70; mm and 0.25; mm to 3; mm thick, even more typically from about 50; mm to 100; mm by 25; mm to 50; mm and 0.5; mm to 1; mm thick.
- a film is characterized by removing most air bubbles prior to or while molding a thin layer of material.
- the film shape may be flat or may follow a 3D contoured shape.
- the film may be created in a single layer or by laminating multiple layers of material.
- the dimensions are typically from about 10; mm to 100; mm diameter and 1; mm to 10; mm thick, more typically from about 30; mm to 80; mm diameter and 2; mm to 8; mm thick, even more typically from about 55; mm to 65; mm diameter and 2.5; mm to 5; mm thick.
- a disk can be described as a cylinder with nominal diameter greater than nominal height.
- the nominal outer body dimensions are typically up to about 100; mm by 100; mm and 25; mm thick, more typically up to about 50; mm by 70; mm and 20; mm thick, even more typically up to about 30; mm by 50; mm and 15; mm thick.
- a molded 3D shape is typically defined so as to fit into a particular anatomical feature or surgically created space, such as a dental cavity, a drilled tunnel in a bone, or the space between two vertebral bodies in the spine.
- the dimensions are typically from about 10; mm to 100; mm diameter and 1; mm to 10; mm tall, more typically from about 2; mm to 20; mm diameter and 5; mm to 50; mm tall, even more typically from about 4; mm to 15; mm diameter and 7; mm to 40; mm tall.
- a plug may be described as a cylinder or extruded 2D shape, such as a square, triangle, star, or polygon, with nominal height greater than nominal diameter or characteristic width of the 2D shape.
- the dimensions are typically up to about 500 mm by 500; mm and 50; mm thick, more typically up to about 100; mm by 100; mm and 20 mm thick, even more typically up to about 50; mm by 50; mm and 10; mm thick.
- the outside body dimensions are typically up to about 100; mm by 100; mm and 15; mm thick, more typically up to about 50; mm by 50 nun and 5; mm thick, even more typically up to about 25; mm by 25; mm and 2.5; mm thick.
- the cross section of such a gasket may take any shape including a rectangle, square, triangle, other polygon, circle, half circle, ellipse, or partial ellipse, tracing the entire periphery or some portion of the outside body shape.
- the muscle-based composition and the tissue graft/implant of the present invention comprise a matrix that is formed from the fibers of defatted, shredded, allogeneic human muscle tissue. Due to the fibrous nature of the muscle tissues, the matrix that is formed is porous and particularly well suited both for the infiltration by colonizing cells, and for the storage and slow release of seeded cells, tissue growth factors, and chemotactic agents that attract a desired cell.
- composition or implant/tissue graft of the present invention be combined with a natural or recombinant growth factor to stimulate tissue growth and healing, or a chemotactic agent to attract a desired cell. It is also within the scope of the present invention that the composition or tissue graft/implant of the present invention be seeded with one or more cells prior to implantation into the patient. When the composition or tissue graft/implant of the present invention is to be used as a tissue graft for skin, it is typically seeded with fibroblasts, preferably with melanocytes.
- composition or tissue graft/implant of the present invention When the composition or tissue graft/implant of the present invention is to be used to treat a defect or an injury to a bone, it is seeded with osteogenic cells.
- the composition or tissue graft/implant of the present invention is to be used to treat any tissue defect or injury, it is seeded with stem cells that will provide the native cells necessary for restoration of the injury or defect.
- tissue grafts and implants of the present invention exhibit a great degree of tensile strength. They are readily stitchable and retain a majority of their tensile strength even when rehydrated.
- tissue grafts and implants of the present invention are moldable and suitable for filling in irregular gaps or holes in the tissue to be repaired. Typically, the hydrated tissue is press fitted by the surgeon into the defect or cavity to be filled.
- the present invention is directed to a method for making a (muscle-based) composition or a tissue implant suitable for treating an injury or a surgical or medical condition in a human patient, wherein the tissue implant comprises a matrix of digested allogeneic human muscle.
- the method comprises the steps of:
- the matrix of digested allogeneic human muscle comprises from about 1% to about 100% of the final weight of the composition or implant, more typically from 50% to about 99% of the final weight of the implant, even more typically from 75% to about 99% of the final weight of the implant.
- the muscle tissue slurry that is used to make the composition and implant of the present invention is the subject of copending parent application, U.S. Ser. No. 10/754,310, filed Jan. 9, 2004, and incorporated herein by reference in its entirety.
- the muscle tissue slurry has a viscosity within the range of 1; centistoke to 20,000; centistokes when measured at 25° C.
- the muscle tissue slurry has a viscosity within the range of 1; centistoke to 10,000; centistokes when measured at 25° C.; more typically, the muscle tissue slurry has a viscosity within the range of 1; centistoke to 5,000; centistokes when measured at 25° C.
- the muscle tissue slurry that is used to make the composition and/or tissue graft/implants of the present invention is also characterizable in terms other than viscosity.
- the muscle tissue slurry is characterized instead by the ratio of the volume of aqueous carrier (milliliters) to dry weight of muscle (grams).
- the aqueous carrier is acidic, basic or neutral.
- the aqueous carrier is an aqueous acidic solution (“an acid”).
- the ratio of acid (volume) to dry weight of muscle (grams) is within the range of 100:1; to 10:1;; more typically within the range of 80:1; to 20:1;; most typically within the range of 70:1; to 30:1.
- the choice of the ratio of acid to protein determines the viscosity of the slurry and the choice is based upon the ultimate application of the slurry.
- the muscle tissue slurry of the present invention was used to make the various tissue implants and grafts (collectively “implants”) disclosed further herein.
- the source of the muscle is typically donor muscle that is obtained from cadavers and thus, the muscle is allogeneic. While the present invention is discussed herein in terms of an allogeneic human muscle source and being used for preparing a tissue implant for humans, any non-human mammal may be used as the muscle donor and the resulting slurry used to prepare a xenogeneic implant for use in a human or in another species of mammal.
- Preferred xenogeneic muscle sources are porcine and bovine. Pigs are currently being used to generate minimally antigenic hearts suitable for implantation as living heart transplants in humans.
- the applicants disclose that they ectopically implanted into a rat a tissue matrix (in the form of a sponge) that was derived from human donor muscle and the tissue matrix was resorbed over a period of time without inducing an inflammatory response.
- tissue matrix in the form of a sponge
- This establishes the functionality of the tissue matrix as a biocompatible resorbable tissue scaffold even when implanted (as a xenograft) in a different species.
- the intermediate composition of the present invention would produce an acceptable tissue matrix even when made from xenograft muscle tissue.
- the muscle tissue is defatted prior to or after being shredded.
- it is defatted prior to being shredded.
- the donor muscle is cut into chunks of sufficiently small size (e.g., 20; mm ⁇ 20; mm) to allow the tissue to be easily defatted.
- Suitable methods for defatting tissue are well known in the art. Typically, this involves treating the tissue with a fat dissolving substance such as 60% to 90% alcohol in water. See U.S. Pat. No. 5,846,484, entitled “Pressure flow system and method for treating a fluid permeable workpiece such as a bone,” which issued to Scarborough, et al. on Dec. 8, 1998.
- the defatted allogeneic human muscle tissue was dried, more preferably by lyophilization, to facilitate further processing, such as shredding.
- the lyophilization process need not remove all of the water. While the water content of the chopped allogeneic muscle can vary, it is typically dried to about 3% moisture content by weight. It is especially preferred that the allogeneic human muscle tissue be defatted prior to lyophilization.
- the defatted and dried muscle tissue was shredded to a coarse fiber.
- Shredding is accomplished by any commercial shredder. Suitable shredders include coffee grinders, food processors, and the like.
- the shredded muscle tissue was mixed vigorously with a biocompatible acid to produce the muscle slurry that is the intermediate composition of the present invention.
- mixing was accomplished with a hand-held food processor. Mixing takes from 15; seconds to over two minutes and is dependent upon the amount of shredded protein and the volume of acid. Mixing should continue until the slurry has uniform consistency.
- the slurry is preferably degassed. Degassing was accomplished by centrifugation, or possibly vacuum centrifugation.
- the biocompatible acid is either a biocompatible organic acid or a biocompatible inorganic acid.
- a suitable biocompatible acid is selected from the group consisting of acetic acid, citric acid, formic acid, hydrochloric acid, lactic acid, phosphoric acid, phosphorus acid and sulfuric acid. More preferably, the biocompatible acid is an organic acid; most preferably the organic acid is acetic acid. The function of the acid is to partially digest the muscle tissue.
- the intermediate composition employed in the present invention is implantable in liquid form, such as by injecting into the patient at a site in need of restoration. In another embodiment, it is dried to a predetermined shape to prepare a variety of tissue implants.
- the present invention is directed to a tissue graft of implant suitable for treating an injury or a surgical or medical condition in a human patient, wherein the tissue implant comprises a matrix of digested allogeneic human muscle.
- the matrix of digested allogeneic human muscle comprises from about 1% to about 100% of the dry weight of the implant, more typically from 15% to about 95% of the dry weight of the implant, even more typically from 25% to about 85% of the dry weight of the implant.
- the method of making a composition or tissue implant of the present invention further comprises combining the allogeneic human muscle with a demineralized bone matrix (DBM), mineralized bone matrix, cortical cancellous chips (CCC), crushed cancellous chips, tricalcium phosphate, hydroxyapatite, or biphasic calcium phosphate and/or shredded allogeneic human tendon.
- DBM demineralized bone matrix
- CCC cortical cancellous chips
- crushed cancellous chips tricalcium phosphate, hydroxyapatite, or biphasic calcium phosphate and/or shredded allogeneic human tendon.
- the tissue implant of the present invention contains DBM, mineralized bone matrix, CCC, crushed cancellous chips, tricalcium phosphate, hydroxyapatite, or biphasic calcium phosphate or a combination thereof
- the resulting tissue implant is osteogenic and particularly suited for repairing bone.
- the implant of this embodiment also exhibits improved dimensional stability and ability to hold shape during drying, rehydration and handling.
- the DBM, mineralized bone matrix, CCC, crushed cancellous chips, tricalcium phosphate, hydroxyapatite, or biphasic calcium phosphate or a combination thereof are dispersed equally or randomly throughout the matrix.
- the DBM, mineralized bone matrix, CCC, crushed cancellous chips, or both are sandwiched between layers of the matrix to form a laminate implant.
- the DBM, mineralized bone matrix, CCC, crushed cancellous chips, tricalcium phosphate, hydroxyapatite, or biphasic calcium phosphate or a combination thereof typically constitute from 1% to 99%, more typically from 50% to 99%, most typically from 90% to 99% of the dry weight of the composition or implant.
- the tissue implant When the tissue implant contains tendon, it is tougher and stronger than the digested human muscle matrix alone and is particularly suited as a dressing for a wound or bum that will become infiltrated with skin cells and allow for development of a replacement skin layer that will cover the wound or bum.
- the ratio of tendon to intermediate composition ranges from 1:99; to 99:1; by dry weight. Typically, the range is 10:90; to 90:10;; more typically, the range is 25:75; to 75:25. While the above discussion is in relation to “tendon,” which is a preferred source of collagen for this invention, it is intended that any collagen source be used, including tendon, fascia and dermis.
- the resulting intermediate composition (the digested allogeneic human muscle slurry) of the present invention is optionally degassed, by pouring the slurry into plates or tubes, and centrifuging them to eliminate any entrapped air and produce a higher density slurry.
- the slurry is poured into a mold for formation of an implantable tissue matrix of any size or shape.
- the slurry can be combined with other agents, such as DBM, CCC or a collagen (e.g., tendon, fascia) slurry before being poured into the mold.
- the freeze dried composition, tissue graft or implant of the present invention is removed from its sterile packaging and rehydrated by contacting them with water, saline, blood, plasma, a buffered solution, or any other suitable liquid.
- the rehydrating liquid contains a growth factor or a chemotactic agent as discussed above.
- the slurry is poured into a mold for formation of an implantable tissue matrix of any size or shape.
- the slurry can be combined with other agents, such as DBM, mineralized bone matrix, CCC, crushed cancellous chips, or a collagen (e.g., tendon, fascia, or dermis) slurry before being poured into the mold.
- DBM mineralized bone matrix
- CCC crushed cancellous chips
- a collagen e.g., tendon, fascia, or dermis
- a thin layer of the slurry is poured in a flat plate and the slurry is either air dried, air dried with positive airflow, or dried in an oven, preferably a convection oven.
- the slurry (neat or amended) is poured into a mold of the appropriate shape, frozen (to retain its size), and lyophilized.
- the resulting dried implantable film or shape is then ready for packaging and final sterilization.
- Shrinkage of the material during drying is noted, especially as characteristic thickness and bulk of the implant increase. Shrinkage results in changes in shape, density, uniformity, thickness, appearance, and residual stresses of the implants. Shrinkage and its effects can be controlled and manipulated by careful control of parameters including drying time, thickness of implant sections, shape of implant, coring or segmenting of thick sections, and shape and configuration of molds. Other process parameters directly affecting the finished product include order of process steps, spatial orientation of the graft during processing, and method of application of the slurry into the molds.
- the present invention is directed to a method for making the intermediate composition (muscle tissue slurry) of the present invention comprising the steps of:
- the tendon that is used in the tissue implants of the present invention is processed the same as the allogeneic human muscle. It is chopped into pieces, defatted, freeze dried (lyophilized), shredded into a coarse fiber, and acid digested to provide a viscous tendon digestate that is suitable for combining with the acid digested allogeneic muscle (intermediate composition) of the present invention.
- the ratio of tendon digestate to intermediate composition ranges from 1:99; to 99:1. Typically, the range is 10:90; to 90:10;; more typically, the range is 25:75; to 75:25. While the above discussion is in relation to “tendon,” which is a preferred source of collagen for this invention, it is intended that any collagen source be used, including fascia.
- the collagen source is xenogeneic or allogeneic. Preferably, it is allogeneic.
- Skeletal muscle was removed from a donor cadaver and cut into chunks (20; mm ⁇ 20; mm).
- the chunks of skeletal muscle were defatted, deantigenized and soluble protein was removed by subjecting the muscle tissue to cyclically alternating pressure and vacuum in the sequential presence of the isopropyl alcohol, hydrogen peroxide and a detergent.
- the method is fully described in assignee's U.S. Pat. No. 6,613,278, entitled “Tissue Pooling Process,” which issued to Mills et al., on Sep. 2, 2003;; U.S. Pat. No. 6,482,584, entitled “Cyclic implant perfusion cleaning and passivation process,” which issued to Mills, et al. on Nov. 19, 2002;; and U.S. Pat.
- the combined acid solution and muscle tissue were mixed with a high speed mixer until a uniform gel (i.e., slurry) was formed. Mixing took between 15; seconds to more than 2; minutes depending upon the acid concentration, amount of muscle tissue and volume of acid solution.
- the above described slurry was used alone or combined with another component to make a tissue implant of the present invention.
- the lower viscosity (more dilute) slurries were preferred when making pourable/flowable films.
- the lower to intermediate viscosity slurries were more desirable when being combined with DBM or CCC or tendon, each of which thickened the slurry.
- tendon/skeletal muscle slurries Three identical tendon/skeletal muscle slurries were poured into molds, frozen, and lyophilized. The lyophilized frozen slurries produced tendon/skeletal muscle based implants in the form of a sponge.
- a series of implantable sponges were made as specified in Examples 1, 2, 3, and 4; above. Using appropriate molds, the sponges were made in a square, circular, or hexagonal forms. The average thickness was 5; mm. The squares were as large as 50; mm by 50; mm. The circles had diameters as large as 90; mm. The hexagons were 40; mm per side.
- An implant following the method of Example 2 can be formed in a mold created by known methods from digitized data of an area in need of treatment.
- Methods of mold creation are known in the art, and can include x-ray, ultrasound, or cat-scan imaging data translated to a computer aided design (CAD) or computer aided manufacturing (CAM) or computer numerical controlled (CNC) machining center.
- CAD computer aided design
- CAM computer aided manufacturing
- CNC computer numerical controlled
- the implants made from these methods could be used to treat conditions where exact matching of the anatomical structure is critical and where a biocompatible allograft implant is beneficial.
- Applications can include facial reconstruction, general orthopedic defects and bone segment replacements, and vertebral body replacements.
- Example 2 An implant following the method of Example 2; was partially rehydrated with sterile saline solution after drying. The implant was placed into a cavity and molded to the shape of the cavity under manual manipulation. The implant molded to the shape of the cavity and then retained that shape under minimal forces including gravity and light rinsing.
Abstract
Description
-
- i. removing the fat and soluble proteins from allogeneic or xenogeneic mammalian muscle tissue;
- ii. lyophilizing the muscle tissue from step (i);
- iii. shredding the lyophilized muscle tissue;
- iv. mixing the shredded muscle tissue in an aqueous carrier to form a muscle tissue slurry having a viscosity within the range of 1; centistoke to 20,000; centistokes;
- v. transferring the muscle tissue slurry to an appropriate shaped mold; and
- vi. drying the slurry in the mold to form the correspondingly shaped tissue implant.
-
- i. removing the fat and soluble proteins from allogeneic or xenogeneic mammalian muscle tissue;
- ii. lyophilizing the muscle tissue from step (i);
- iii. shredding the lyophilized muscle tissue;
- iv. mixing the shredded muscle tissue in an aqueous carrier to form a muscle tissue slurry having a viscosity within the range of 1; centistoke to 20,000 centistokes;
- v. transferring the muscle tissue slurry to an appropriate shaped mold; and
- vi. drying the slurry in the mold to form the correspondingly shaped tissue implant.
-
- i. removing the fat and soluble proteins from allogeneic or xenogeneic mammalian muscle tissue;
- ii. lyophilizing the muscle tissue from step (i);
- iii. shredding the lyophilized muscle tissue; and
- iv. mixing the shredded muscle tissue in an aqueous carrier to form a muscle tissue slurry having a viscosity within the range of 1; centistoke to 20,000 centistokes.
TABLE 1 |
Ratios of Acetic Acid (ml) to weight of dry muscle (g) |
Muscle (g) | Muscle (g) | Muscle (g) | |||
Acid | Acid:muscle | Acid:muscle | Acid:muscle | ||
10% acetic acid | 0.5 g | 0.75 g | 1 g | ||
46:1 | 34:1 | 22:1 | |||
20% acetic acid | 0.5 g | 0.75 g | 1 g | ||
46:1 | 34:1 | 22:1 | |||
Claims (9)
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/807,599 US8394141B2 (en) | 2004-01-09 | 2010-09-09 | Connective-tissue-based or dermal-tissue-based grafts/implants |
US13/815,184 US8747467B2 (en) | 2004-01-09 | 2013-02-07 | Muscle-based grafts/implants |
US14/284,918 US9398948B2 (en) | 2004-01-09 | 2014-05-22 | Connective-tissue-based or dermal-tissue-based grafts/implants |
US15/192,368 US10022472B2 (en) | 2004-01-09 | 2016-06-24 | Connective-tissue-based or dermal-tissue-based grafts/implants |
US16/036,594 US10814034B2 (en) | 2004-01-09 | 2018-07-16 | Connective-tissue-based or dermal-tissue-based grafts/implants |
US17/080,509 US11779680B2 (en) | 2004-01-09 | 2020-10-26 | Connective-tissue-based or dermal-tissue-based grafts/implants |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/754,310 US7001430B2 (en) | 2004-01-09 | 2004-01-09 | Matrix composition for human grafts/implants |
US10/793,976 US7131994B2 (en) | 2004-01-09 | 2004-03-05 | Muscle-based grafts/implants |
US11/480,711 US20060251629A1 (en) | 2004-01-09 | 2006-07-03 | Muscle-based grafts/implants |
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US12/807,599 Expired - Lifetime US8394141B2 (en) | 2004-01-09 | 2010-09-09 | Connective-tissue-based or dermal-tissue-based grafts/implants |
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Also Published As
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US8747467B2 (en) | 2014-06-10 |
US20110091516A1 (en) | 2011-04-21 |
US20210046215A1 (en) | 2021-02-18 |
US10814034B2 (en) | 2020-10-27 |
US20140257516A1 (en) | 2014-09-11 |
US20180326119A1 (en) | 2018-11-15 |
US20060251629A1 (en) | 2006-11-09 |
US20160317708A1 (en) | 2016-11-03 |
US7883541B2 (en) | 2011-02-08 |
US9398948B2 (en) | 2016-07-26 |
WO2005070328A1 (en) | 2005-08-04 |
US10022472B2 (en) | 2018-07-17 |
US20130149356A1 (en) | 2013-06-13 |
US20080077252A1 (en) | 2008-03-27 |
US11779680B2 (en) | 2023-10-10 |
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